Research: The tumor necrosis factor receptor superfamily is comprised of a number of related cell surface molecules which play crucial roles in regulating the balance between cell proliferation and cell death. Deregulation of one of these receptors, CD30, has been implicated in several disorders including Hodgkins disease and anaplastic large cell lymphoma. Activation of CD30 by its cognate ligand or by crosslinking with agonistic antibodies can induce either proliferation or apoptotic cell death, depending upon the cellular context, although the molecular basis of this disparity is unknown.We and others have identified two distinct families of signaling intermediates which are utilized by CD30. The first of these are the TNF receptor-associated factors (TRAFs), which bind to elements in the cytoplasmic domains of CD30, CD40, and the type 2 TNF receptor, and have been shown to activate the pleiotropic transcription factor NF kappa B, as well as the JNK (c-Jun NH<SUB>2</SUB>-terminal kinase) family of serine-threonine kinases. Both NF kappa B and JNK have been implicated in the regulation of cell survival. We have recently identified a Drosophila TRAF homolog, DroTRAF1, thus revealing the high degree of conservation of these molecules thoughout evolution. DroTRAF1 is a potent activator of JNK and plays a pivotal role in the establishment of the central and peripheral nervous systems in the fly.The second group of proteins known to be involved in CD30 signal transduction are the IAPs (inhibitors of apoptosis). The iapgenes were first discovered in insect viral genomes, where they are required for maximal infectivity, but similar to the TRAFs, the iapshave been highly conserved throughout evolution, with close homologs identified in Drosophila, mouse, and human genomes. Several human iapgenes have been identified, but two of these, cIAP1 and cIAP2, can be recruited to the CD30 signaling complex through direct binding to TRAF proteins, and can also regulate JNK and NF kappa B activity. cIAP2 was recently identified in a t(11;18)(q21;q21) translocation in human mucosa-associated lymphoid tissue (MALT) lymphoma.Using molecular genetic techniques, we are examining the roles of the TRAFs and IAPs in the activation of NF kappa B and JNK, with a particular focus on CD30. Using the yeast two-hybrid system we have cloned novel IAP-interacting factors which are recruited into the CD30 complex. We are defining the protein-protein interactions between these factors and the different components of the CD30 signaling complexes in order to better understand their role in lymphomagenesis. - apoptosis, IAP, TRAF, lymphoma,